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Natural Killer T (NKT) cells have been described as T lymphocytes expressing NK receptors
such as NK1.1. This lymphocyte subset consists of several subpopulations, each with
distinct characteristics [1,2]. Unlike conventional T cells, the vast majority of mouse NKT cells recognize glycolipid
antigens including α-galactosylceramide (α-GalCer), a glycosphingolipid originally
isolated from marine sponges that can not be found in mammalian cells [3]. α-GalCer is presented by an MHC class I like antigen presenting molecule, CD1d.
Several studies have highlighted the unique features of NKT cells, because their T
cell receptor (TCR) repertoire is highly skewed with an invariant TCR-α rearrangement,
Vα14-Jα18. In humans, a similar NKT cell subset with an invariant TCR-α chain, Vα24,
exists. Therefore, these cells are often referred to as Vαi NKT cells.

A characteristic feature of Vαi NKT cells is their rapid production of large quantities of both Th1 and Th2 cytokines
upon stimulation. These cells, therefore, may profoundly regulate the immune system:
they may either enhance or suppress immune responses [4]. Several groups have investigated whether Vαi NKT cells are relevant for the pathogenesis of autoimmune diseases. There is evidence
suggesting that Vαi NKT cells naturally influence autoimmunity and from other experiments it appeared
that a vigorous but unnatural activation of Vαi NKT cells by α-GalCer is required to elicit their regulatory function. For example,
in type 1 diabetes Vαi NKT cells are considered to be protective [5], although some conflicting reports exist [6,7]. Vαi NKT cells are also considered to be of relevance in the pathogenesis of other autoimmune
diseases such as multiple sclerosis, systemic lupus erythematosus and experimental
colitis although their precise role in these diseases remains unclear at present [4]. Few data exist on the putative role of Vαi NKT cells in the pathogenesis of rheumatoid arthritis (RA). It has been reported that
RA patients have abnormalities in the number and function of Vαi NKT cells that are CD4-CD8- in peripheral blood lymphocytes compared to healthy individuals, suggesting a protective
role for these cells in RA [8], although indirect effects induced by for example therapy have not been ruled out.

Due to their immunomodulatory properties, manipulation of Vαi NKT cell mediated responses is an attractive potential therapeutic strategy for the
treatment of autoimmune diseases [4]. This is illustrated by the beneficial effects of α-GalCer treatment in experimental
models of autoimmune diseases. Interestingly, the CD1d system is highly conserved
throughout mammalian evolution, which is illustrated by the ability of CD1d glycolipid
antigens such as α-GalCer to stimulate both mouse and human Vαi NKT cells [9]. In addition, all human individuals have these cells with identical specificity,
and α-GalCer specifically targets them with little toxicity in humans [10]. Nevertheless, administration of α-GalCer also has some disadvantages such as the
simultaneous stimulation of both Th1 and Th2 cytokines. This problem could be circumvented
by designing analogues of α-GalCer that are still able to stimulate Vαi NKT cells but give rise to an altered immune response compared to that induced by
α-GalCer. An analogue of α-GalCer with a truncated sphingosine tail, OCH, was reported
to preferentially promote IL-4 secretion and to be more potent than α-GalCer in preventing
autoimmune encephalomyelitis [11]. Likewise, repeated administration of OCH, compared to α-GalCer, resulted in a substantial
improvement of joint swelling and inflammation in collagen induced arthritis [12]. Therefore, inducing a polarization in the cytokine response induced by Vαi NKT cells by altered glycolipid CD1d antigens has sparked the interest of many researchers
as a therapeutic strategy to treat autoimmune diseases.

Until now it was generally believed that Vαi NKT cells had a protective role in RA. However, a recent paper by Kim et al ., challenged this concept by examining the role of Vαi NKT cells in antibody-induced arthritis in the K/BxN serum transfer model [13]. Transfer of serum or immunoglobulins from K/BxN mice to healthy mice causes inflammatory
arthritis by deposition of autoantibody in joint spaces, inducing an inflammatory
cascade with activation of complement and Fcγ receptor pathways [14]. This model is considered to be reminiscent of the terminal effector mechanisms of
RA. The development of antibody-induced arthritis was first examined in Jα18-/- and CD1d-/- mice and was found to be less severe compared to wild-type controls. In addition,
adoptive transfer of NKT cells from C57BL/6 mice into CD1d-/- mice reversed the observed reduction in inflammatory arthritis, illustrating the disease
perpetuating role of Vαi NKT cells in this model. Conversely, stimulation by repeated in vivo administration of α-GalCer resulted in a moderate increase in clinical paw swelling
although no histological analysis was performed. The dual functionality of Vαi NKT cells observed in the K/BxN serum transfer model versus collagen-induced arthritis
may reflect a distinct role for these cells in different phases of RA, with a suppressive
role in the induction phase and a provocative role in antibody-induced joint inflammation.

A particularly fascinating and novel aspect of the current report is the notion that
Vαi NKT cells may actively contribute to synovial inflammation by residing in a niche
where they are usually absent. Hence, Vαi NKT cells were reported to appear within the synovium of wild-type mice as early as
three days after serum transfer. Their appearance results in important alterations
in cytokine balances within the joints. In CD1d-/- mice a marked increase in transcripts of transforming growth factor-beta 1 (TGF-β1)
was observed, contrary to C57BL/6 mice in which the levels were found to be reduced.
By contrast, IL-4 and to a lesser extent IFN-γ transcripts were found to be reduced
in CD1d-/- mice versus controls. However, no differences in transcript levels of either TGF-β1,
IFN-γ or IL-4 were apparent in the spleen. The crucial role of TGF-β1 in mediating
the observed effect in NKT cell deficient animals was shown by in vivo neutralization studies in which anti-TGF-β1 treatment was shown to abrogate the protective
effect of Vαi NKT cells in CD1d-/- mice, while not affecting joint inflammation in wild-type animals. Although several
studies have highlighted important immunoregulatory properties for TGF-β1 in experimental
arthritis, the cellular communication network that results in TGF-β1 secretion is
only partially understood. Kim et al ., propose that Vαi NKT cells suppress the production of TGF-β1 by synovial cells through the production
of IFN-γ or IL-4. Whereas IFN-γ has been known to be a negative regulator for TGF-β1
for many years, the role of IL-4 reported by Kim et al . is unexpected and warrants further investigation [15]. Likewise, the precise mechanism(s) by which Vαi NKT cells are attracted to synovial tissue and the reason(s) why they get activated
locally in the K/BXN serum transfer model to induce TGF-β1 have yet to be elucidated.

Taken together, the data illustrate the multifaceted roles of Vαi NKT cells in autoimmune diseases, particularly RA, and underline the important and
non redundant role of these innate-like lymphocytes in immune regulation.